by Carl Zimmer
The human rhinovirus spreads by making noses run. People with colds wipe their noses, get the virus on their hands, and then spread the virus onto door knobs and other surfaces they touch. The virus hitches onto the skin of other people who touch those surfaces and then slips into their body, usually though their nose. Rhinoviruses can invade the cells that line the interior of the nose, throat, or lungs. They trigger the cells to open up a trapdoor through which they slip. Over the next few hours, a rhinovirus will use its host cells to make copies of its genetic material and protein shells to hold them. The host cell then rips apart, and the new virus escapes.
Rhinoviruses infect relatively few cells, causing little real harm. So why can they cause such miserable experiences? We have only ourselves to blame. Infected cells release special signaling molecules, called cytokines, which attract nearby immune cells. Those immune cells then make us feel awful. They create inflammation that triggers a scratchy feeling in the throat and leads to the production of a lot of mucus around the site of the infection. In order to recover from a cold, we have to wait not only for the immune system to wipe out the virus but also to calm itself down.
The Egyptian author of the Ebers papyrus wrote that the cure for resh was to dab a mixture of honey, herbs, and incense around the nose. In seventeenth-century England, cures included a blend of gunpowder and eggs and of fried cow dung and suet. Leonard Hill, the physiologist who believed a change of temperature caused colds, recommended that children start their day with a cold shower. Today, doctors don’t have much more to offer people who get colds. There is no vaccine. There is no drug that has consistently shown signs of killing the virus. Some studies have suggested that taking zinc can slow the growth of human rhinoviruses, but later studies failed to replicate their results.
In fact, some treatments for the cold may be worse than the disease itself. Parents often give their children cough syrup for colds, despite the fact that studies show it doesn’t make people get better faster. But cough syrup also poses a wide variety of rare yet serious side effects, such as convulsions, rapid heart rate, and even death. In 2008, the Food and Drug Administration warned that children under the age of two—the people who get colds the most—should not take cough syrup.
Another popular treatment for the cold is antibiotics, despite the fact that they only work on bacteria and are useless again viruses. In some cases, doctors prescribe antibiotics because they’re not sure whether a patient has a cold or a bacterial infection. In other cases, they may be responding to pressure from worried parents to do something. But unnecessary prescriptions of antibiotics are a danger to us all, because they foster the evolution of increasingly drug-resistant bacteria in our bodies and in the environment. Failing to treat their patients, doctors are actually raising the risk of other diseases for everyone.
One reason the cold remains incurable may be that we’ve underestimated the rhinovirus. It exists in many forms, and scientists are only starting to get a true reckoning of its genetic diversity. By the end of the twentieth century, scientists had identified dozens of strains, which belonged to two great lineages, known as HRV-A and HRV-B. In 2006, Ian Lipkin and Thomas Briese of Columbia University were searching for the cause of flu-like symptoms in New Yorkers who did not carry the influenza virus. They discovered that a third of them carried a strain of human rhinovirus that was not closely related to either HRV-A or HRV-B. Lipkin and Briese dubbed it HRV-C, and since then, researchers have found that this third lineage is common around the world. From one region to another, the variations in HRV-C’s genes are few, which suggests that the virus wasted no time spreading through our species. In fact, the common ancestor of all HRV-C may be just a few centuries old.
The more strains of rhinoviruses scientists discover, the better they come to understand their evolution. All human rhinoviruses share a core of genes that have changed very little as the viruses have spread around the world. Meanwhile, a few parts of the rhinovirus genome are evolving very quickly. These regions appear to help the virus avoid being killed by our immune systems. When our bodies build antibodies that can stop one strain of human rhinovirus, other strains can still infect us because our antibodies don’t fit on their surface proteins. Consistent with this hypothesis is the fact that people are typically infected by several different human rhinovirus strains each year.
The diversity of human rhinoviruses makes them a very difficult target to hit. A drug or a vaccine that attacks one protein on the surface of one strain may prove to be useless against others that have a version of that protein with a different structure. If another strain of human rhinovirus is even a little resistant to such treatments, natural selection can foster the spread of new mutations, leading to much stronger resistance.
Despite the diversity of rhinoviruses, some scientists are optimistic that they can develop a cure for the common cold. The fact that all strains of human rhinoviruses share a common core of genes suggests that the core can’t withstand mutations. In other words, viruses with mutations in the core die. If scientists can figure out ways to attack the rhinovirus core, they may be able to stop the disease. One promising target is a stretch of genetic material in rhinoviruses that folds into a loop shaped like a clover leaf. Every rhinovirus scientists have studied carries the same clover-leaf structure, which appears to be essential for speeding up the rate at which a host cell copies rhinovirus genes. If scientists can find a way to disable the clover leaf, they may be able to stop every cold virus on Earth.
But should they? Human rhinoviruses certainly impose a burden on public health, not just by causing colds but by opening the way for more harmful pathogens. But the human rhinovirus itself is relatively mild. Most colds are over in a week, and 40 percent of people who test positive for rhinoviruses suffer no symptoms at all. In fact, human rhinoviruses may offer some benefits to their human hosts. Scientists have gathered a great deal of evidence that children who get sick with relatively harmless viruses and bacteria may be protected from immune disorders when they get older, such as allergies and Crohn disease. Human rhinoviruses may help train our immune systems not to overreact to minor triggers, instead directing their assaults to real threats. Perhaps we should not think of colds as ancient enemies but as wise old tutors.
Looking Down from the Stars
Influenza Virus
Influenza. If you close your eyes and say the word aloud, it sounds lovely. It would make a good name for a pleasant, ancient Italian village. Influenza is, in fact, Italian (it means influence). It is also, in fact, an ancient name, dating back to the Middle Ages. But the charming connotations stop there. Medieval physicians believed that stars influenced the health of their patients, sometimes causing a mysterious fever that swept across Europe every few decades. And ever since, influenza has raged through our species. In 1918, a particularly virulent outbreak of the flu killed an estimated fifty million people. Even in years without an epidemic, influenza takes a brutal toll. Each winter, thirty-six thousand people die of the flu in the United States alone; somewhere between a quarter million and a half million people die worldwide. Today scientists know that influenza is not the work of the heavens, but of a microscopic virus. Like cold-causing rhinoviruses, influenza viruses manage to wreak their harm with just ten genes. They spread in the droplets sick people release with their coughs, sneezes, and running noses. A new victim may accidentally breathe in a virus-laden droplet or pick it up on a doorknob and then bring now-contaminated fingers in contact with their mouth. Once a flu virus gets into the nose or throat, it can latch onto a cell lining the airway and slip inside. As flu viruses spread from cell to cell in the lining of the airway, they leave destruction in their wake. The mucus and cells lining the airway get destroyed, as if the flu viruses were a lawn mower cutting grass.
In healthy people, the immune system is able to launch a counterattack in a matter of days. In such cases, the flu causes a wave of aches, fevers, and fatigue, but the worst of it is over within a week. In a small frac
tion of its victims, the flu virus opens the way for more serious infections. Normally, the top layer of cells serves as a barrier against a wide array of pathogens. The pathogens get trapped in the mucus, and the cells snag them with hairs, swiftly notifying the immune system of intruders. Once the influenza lawnmower has cut away that protective layer, pathogens can slip in and cause dangerous lung infections, some of which can be fatal.
For a virus that has caused so much death in the past, and which continues to claim so many victims each year, influenza virus remains surprisingly mysterious. Seasonal flu is most dangerous for people with weak immune systems that can’t keep the virus in check—particularly young children and the elderly. But in flu pandemics, like the 1918 outbreak, people with strong immune systems proved to be particularly vulnerable. Scientists don’t know why the flu switches targets this way. One theory holds that certain strains of the flu provoke the immune system to respond so aggressively that it ends up devastating the host instead of wiping out the virus. But some scientists doubt this explanation and think the true answer lies elsewhere. Scientists also don’t know when influenza viruses first started making people sick. There certainly are historical records of outbreaks of deadly fevers going back thousands of years, but it’s impossible to know whether influenza viruses caused them, or another species of virus with similar symptoms.
Amidst all the mysteries of the flu, the origin of the virus is clear. It came from birds. Birds carry all known strains of human influenza viruses, along with a vast diversity of other flu viruses that don’t infect humans. Many birds carry the flu without getting sick. Rather than infecting their airways, flu viruses typically infect the guts of birds; the viruses are then shed in bird droppings. Healthy birds become infected by ingesting virus-laden water.
Sometimes strains of bird flu jump the species barrier and become human viruses. But for every successful transition, there are probably many failed crossings. Bird flu viruses are well adapted to infecting their avian hosts and reproducing quickly inside them. Those adaptations make them ill-suited to spreading among humans. Starting in 2005, for example, a strain of flu from birds called H5N1 began to sicken hundreds of people in Southeast Asia. It is much deadlier than ordinary strains of seasonal flu, and so public health workers have been tracking it closely and taking measures to halt its spread. For now, at least, H5N1 can only move from a bird to a human; it cannot move from one human to another.
Unfortunately, a poorly adapted flu virus can evolve into a well-adapted one. Flu viruses are particularly sloppy at replicating their genes, so many new viruses acquire mutations. These mutations are like random changes to the letters in the flu’s recipe. Some of the mutations have no effect on viruses. Some leave them unable to reproduce. But a few mutations give flu viruses a reproductive advantage. Natural selection favors these beneficial mutations, and flu strains can become better at infecting humans as mutation after mutation accumulates. Some mutations help the virus by altering the shape of the proteins that stud the virus shell, allowing them to grab human cells more effectively. Other mutations help the flu virus cope with human body temperature, which is a few degrees cooler than that of birds.
Human influenza viruses have also adapted to a new route from host to host. In birds, the viruses travel from guts to water to guts. In people, the virus moves from airways to droplets to airways. This new route also causes the flu rise and fall with the seasons. In places like the United States, most flu cases occur during the winter. According to one hypothesis, this is because the air is dry enough in those months to allow virus-laden droplets to float in the air for hours, increasing their chances of encountering a new host. In other times of the year, the humidity causes the droplets to swell and fall to the ground.
When a flu virus hitches a ride aboard a droplet and infects a new host, it sometimes invades a cell that’s already harboring another flu virus. And when two different flu viruses reproduce inside the same cell, things can get messy. The genes of a flu virus are stored on eight separate segments, and when a host cell starts manufacturing the segments from two different viruses at once, they sometimes get mixed together. The new offspring end up carrying genetic material from both viruses. This mixing, known as reassortment, is a viral version of sex. When humans have children, the parents’ genes are mixed together, creating new combinations of the same two sets of DNA. Reassortment allows flu viruses to mix genes together into new combinations, as well.
As scientists get a closer look at the genes of flu viruses, they’re discovering that reassortment has played a major role in the natural history of the flu. A quarter of all birds with the flu have two or more virus strains inside them at once. The viruses swap genes through reassortment, and as a result they can move easily between bird species. And sometimes, on very rare occasions, an avian influenza virus can pick up human influenza virus genes through reassortment. That can be a recipe for disaster, because the new strain that results can easily spread from person to person. And because it has never circulated among humans before, no one has any defenses that could slow the new strain’s spread.
Reassortment is important for other reasons than viruses jumping the species barrier. Once bird flu viruses evolve into human pathogens, they continue to swap genes among themselves every flu season. This ongoing reassortment allows the viruses to escape destruction. The longer a flu strain circulates, the more familiar it becomes to people’s immune systems, and the faster they can squelch its spread. But with some viral sex, an old flu strain can pick up less familiar genes and become harder to fight.
Humans are not the only hosts who have picked up flu viruses from birds. Horses, dogs, and several other mammals have also picked it up. And in April 2009, the world became painfully aware that flu viruses also infect pigs. An outbreak of so-called swine flu jumped from pigs to humans. It first surfaced in Mexico and soon spread over the entire planet.
The history of this particular flu strain, called Human/Swine 2009 H1N1, is a tangled tale of genetic mixing and industrialized agriculture. Pigs seem to have just the right biology for reassortment; some of their receptors can easily accept human flu viruses, while other receptors welcome bird flu. Over the past century, pig farms have grown in size and density, so that flu viruses can easily move from host to host and swap genes with other strains. The oldest known swine flu strain emerged around the same time the 1918 pandemic strain entered humans; this so-called classical strain is still making pigs sick. In the 1970s a bird flu strain evolved in Europe or Asia into a new swine flu strain. A different pig-bird mix arose in the United States. And in the late 1990s, American scientists discovered a “triple reassortant” in pigs that mixed genes from all three flu strains.
Once scientists sequenced the genes of the new Human/Swine 2009 H1N1, they realized that it was the product of two different flu viruses: the triple reassortant and a Eurasian bird-to-pig strain. By comparing the new mutations that had arisen from the viruses infecting different patients, researchers have estimated that this new virus first evolved in the fall of 2008. It circulated quietly before coming to light in the spring of 2009.
Because Human/Swine 2009 H1N1 was such a new virus, public health authorities swung quickly into action. The Mexican government essentially shut down the entire country for a time, hoping to prevent the virus from finding new hosts. As Human/Swine 2009 H1N1 turned up in other countries, their governments took actions of their own. By May 2009, it was clear that while the new virus was unusually swift, it was not significantly more dangerous than typical seasonal flu.
As I write in 2010, no one can say if the new strain will fade away, outcompeted by other flu strains, or if it will mutate into a more dangerous form, or experience even more reassortment and pick up new genes. But we are not helpless as we wait to see what evolution has in store for us. We can do things to slow the spread of the flu, such as washing our hands. And scientists are learning how to make more effective vaccines by tracking the evolution of the flu virus so
they can do a better job of predicting which strains will be most dangerous in flu seasons to come. We may not have the upper hand over the flu yet, but at least we no longer have to look to the stars to defend ourselves.
Rabbits with Horns
Human Papillomavirus
The stories about rabbits with horns circulated for centuries. Eventually they crystallized into the myth of the jackalope. If you go to Wyoming and twirl a rack of postcards, chances are you’ll find a picture of a jackalope bounding across the prairie. It looks like a rabbit sprouting a pair of antlers. You may even see jackalopes in the flesh—or at least the head of one mounted on a diner wall.
On one level, it’s all bunk. Most jackalopes are nothing but taxidermic trickery—rabbits with pieces of antelope antler glued to their heads. But like many myths, the tale of the jackalope has a grain of truth buried at its core. Some real rabbits do indeed sprout horn-shaped growths from their heads.
In the early 1930s, Richard Shope, a scientist at Rockefeller University, heard about horned rabbits while on a hunting trip. He had a friend catch one and send him some of the tissue so that he could figure out what it was made of. Shope’s colleague, Francis Rous, had done experiments with chickens that suggested viruses could cause tumors. Many scientists at the time were skeptical, but Shope wondered if rabbit “horns” were also tumors, somehow triggered by an unknown virus. To test his hypothesis, Shope ground up the horns, mixed them in a solution, and then filtered the liquid through porcelain. The fine pores of the porcelain would only let viruses through. Shope then rubbed the filtered solution onto the heads of healthy rabbits. They grew horns as well.